A Novel Adenoviral-Permissive, Immunocompetent Hamster Model to Evaluate Oncolytic Adenoviral Therapy for Glioblastoma

一种新型腺病毒许可、免疫功能正常的仓鼠模型，用于评估胶质母细胞瘤的溶瘤腺病毒治疗

• 批准号: 10593081
• 负责人: FREDERICK F LANG
• 金额: $ 44.54万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593081
• 关键词: Ablation; Address; Adenovirus Infections; Adenoviruses; Adrenal Cortex Hormones; Adult; Animal Model; Animals; Antibodies; Automobile Driving; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cell Line; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Combination immunotherapy; Data; Development; Disease; Effector Cell; Engineering; Evaluation; Exposure to; Gene Targeting; Genetic; Glioblastoma; Glioma; Hamsters; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunologic Memory; Immunotherapy; Impairment; Infection; Intracranial Neoplasms; Laboratories; Malignant Neoplasms; Mediating; Mesenchymal; Mesocricetus auratus; Modeling; Molecular; Mus; Oncogenes; Oncolytic; Oncolytic viruses; Outcome; Patients; Phase I Clinical Trials; Positioning Attribute; Preclinical Testing; Predisposition; Production; Public Health; Publishing; Recurrence; Reproducibility; Research; Research Personnel; Research Project Grants; Solid Neoplasm; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Time; Translational Research; Treatment Efficacy; Tumor Stem Cells; Tumor Suppressor Proteins; Viral; Virus; Virus Replication; Xenograft procedure; anti-tumor immune response; cancer infiltrating T cells; checkpoint inhibition; clinical implementation; combinatorial; efficacy evaluation; experience; immune activation; immune function; immunomodulatory therapies; immunoregulation; improved; in vivo; innovation; molecular subtypes; mouse model; neoplastic cell; nerve stem cell; novel; novel therapeutics; oncolysis; oncolytic adenovirus; oncolytic virotherapy; patient population; permissiveness; pharmacologic; pre-clinical; preclinical study; response; stem cells; translational approach; translational model; treatment strategy; tumor

Despite oncolytic adenoviruses emerging as promising new therapeutics for patients with glioblastoma (GBM), there are no translational mammalian models in an immune competent animal that are permissive to adenoviral infection and that allow for integration of both the oncolytic and immune effects of these viruses. The overall objectives of this proposal are to develop and characterize a Golden hamster model of GBM that addresses the limitations of existing murine models with respect to pre-clinical testing of oncolytic adenoviral therapy. The central hypothesis is that hamster GBM models will provide reliable pre-clinical data to decipher oncolytic adenoviral therapeutic mechanisms and to evaluate preclinical strategies for translation to patients. The rationale for the proposed research is that understanding the interactions between viral oncolysis and the immune system will uncover mechanisms of therapeutic efficacy, identify which patients might respond best, and reveal new combinatorial therapeutic approaches. The central hypothesis will be tested in three specific aims: 1) Develop hamster glioma stem cell (hamGSC) lines that reflect common molecular alteration in human glioma, 2) Characterize the hamster immune response to oncolytic adenovirus, and 3) Evaluate the effects of pharmacological manipulation of the immune system on the efficacy of Delta-24-RGD. In Aim 1, CRISPR gene targeting will be used to create hamGSC lines driven by specific driver alterations to reflect human GBM molecular subtypes. In Aim 2, the immune response to oncolytic adenovirus will be characterized. Using T-cell depletions strategies, the contributions of immune effector cells to oncolytic virus efficacy and long-term immune memory and the impacts of pre-existing exposure to adenovirus will be evaluated. Aim 3 will evaluate the effects of immune function via either corticosteroids or immune checkpoint inhibitors on oncolytic adenovirus therapeutic efficacy. Collectively, the studies proposed in this application will result in the development and characterization of a novel mammalian model for translational evaluation of oncolytic adenovirus in the treatment of GBM. This contribution is significant because it will overcome many limitations of mouse glioma models and for the first time provide a platform for pre-clinical studies to evaluate the efficacy and mechanisms of oncolytic adenoviral therapy against GBM. The proposed research is innovative because this is the first hamster glioma model that is intracranial, immune competent, and adenoviral replication permissive. This represents a distinct advantage over traditional murine models, particularly in the setting of evaluating immune-modulating therapies such as oncolytic adenoviral therapy.

尽管溶瘤腺病毒正在成为胶质母细胞瘤（GBM）患者有希望的新疗法， 在具有免疫能力的动物中没有允许腺病毒的转化哺乳动物模型 感染，并允许整合这些病毒的溶瘤和免疫作用。整体 该提案的目标是开发并描述 GBM 的金仓鼠模型，该模型解决了 现有小鼠模型在溶瘤腺病毒治疗的临床前测试方面的局限性。这 中心假设是仓鼠 GBM 模型将提供可靠的临床前数据来破译溶瘤 腺病毒治疗机制并评估转化为患者的临床前策略。理由 拟议的研究是了解病毒溶瘤作用与免疫系统之间的相互作用 将揭示治疗效果的机制，确定哪些患者可能反应最好，并揭示新的 组合治疗方法。中心假设将在三个具体目标上进行检验： 1) 开发 反映人类神经胶质瘤常见分子改变的仓鼠神经胶质瘤干细胞 (hamGSC) 系，2) 表征仓鼠对溶瘤腺病毒的免疫反应，以及 3) 评估 免疫系统的药理学操作对 Delta-24-RGD 功效的影响。目标1，CRISPR基因 靶向将用于创建由特定驱动程序改变驱动的 hamGSC 系，以反映人类 GBM 分子亚型。在目标 2 中，将对溶瘤腺病毒的免疫反应进行表征。使用T细胞 耗竭策略、免疫效应细胞对溶瘤病毒功效和长期免疫的贡献 将评估记忆和先前接触腺病毒的影响。目标3将评估效果 通过皮质类固醇或免疫检查点抑制剂对溶瘤腺病毒治疗的免疫功能的影响 功效。总的来说，本申请中提出的研究将导致开发和表征 一种新的哺乳动物模型，用于溶瘤腺病毒治疗 GBM 的转化评估。这 贡献是重大的，因为它将克服小鼠神经胶质瘤模型的许多局限性，并且是首次 为评估溶瘤腺病毒治疗的疗效和机制的临床前研究提供平台 对抗 GBM。拟议的研究具有创新性，因为这是第一个仓鼠神经胶质瘤模型 颅内、免疫能力强、腺病毒复制允许。这代表了一个明显的优势 传统的小鼠模型，特别是在评估免疫调节疗法（例如溶瘤疗法）的情况下 腺病毒治疗。